Chronic pain represents a major cause of morbidity, significantly impairing quality of life and imposing a substantial financial and healthcare burden. The wide distribution of a limited range of neurotransmitters, receptors, and ion channels in the nervous system makes it difficult to selectively target pain-related pathways using drugs that are administered systemically. As a result, tolerance, abuse and deleterious side-effects limit the use of all currently available therapeutics.
We have previously used replication-defective HSV-based gene therapy vectors to deliver inhibitory neurotransmitters or gene products that attenuate the action of pro-nociceptive molecules to primary neuronal afferents of the peripheral nervous system (PNS), thereby blocking nociceptive neurotransmission in a variety of pre-clinical pain models [Goss et al., 2001; Goss et al., 2002; Goss et al., 2011; Hao et al., 2006; Hao et al., 2009; Miyazoto et al., 2010; Srinivasan et al., 2008; Wilson et al., 1999; Yokoyama et al., 2009] and more recently in patients [Fink et al., 2011)].
The transient receptor potential cation channel subfamily V member 1 (TRPV1) is one of 28 members of the transient receptor potential (TRP) non-selective cation channel superfamily and an important regulator of primary afferent nociceptive activity and pain signaling [Caterina & Julius, 2001]. TRPV1 can be induced by binding of the agonist capsaicin, as well as by protons and temperatures above 42° C. [Caterina et al., 1997; Tominaga et al., 1998]. TRPV1 has been documented to contribute to the chronic pain state in patients with arthritis, cancer, cystitis, diabetic neuropathy and post-herpetic neuralgia [Brederson et al., 2013; Bohlen & Julius, 2012; Roberson et al., 2011]. TRPV1 is primarily localized to the surface of small unmyelinated C-fibers that are thought to be the primary nociceptors as TRPV1 levels have been associated with thermal hyperalgesia (TH) in inflammatory and neuropathic pain models [for review see Winter et al., 2013].
Over the last decade, a number of gene products have been identified that modulate TRPV1 activity via phosphorylation of residues within the cytoplasmic domains of TRPV1 that assist in sensitization of the receptor. These products include calcium/calmodulin-dependent kinase (CamKinase-II) [Price et al., 2005; Zhang et al., 2011], protein kinase A (PKA) [Lee et al., 2012; Suguira et al., 2004: Varga et al., 2006] and the epsilon isoform of protein kinase C (PKCe) [Hucho et al., 2012]. TRPV1 activity is also modulated in the opposite manner (i.e. desensitization) via dephosphorylation of residues located in the cytosolic domains of the receptor. An established example of a desensitizing molecule is calcineurin, a Ca2+-calmodulin-dependent serine/threonine protein phosphatase, also known as Protein Phosphatase 2B (PP2B) [Chaudhury et al., 2011; Jeske et al., 2006; Mohapatra & Nau, 2005; Por et al., 2010].